The Alcohol Research Center of The Scripps Research Institute (TRSI-ARC) aims at continuing its interdisciplinary program focused on the theme of the central nervous system effects of alcohol. For this renewal application, the TSRI-ARC will be a P60 consisting of 10 components and an Educational Component. Four Core components are proposed: Administrative, Animal Models Development, Biochemical, Clinical, and Pilot. Five research components are proposed: Cellular Neurobiology (Siggins), Neuroendocrinology (Rivier), Neuropharmacology(Weiss), Clinical Neurobehavioral (Ehlers), and Clinical Neurophysiology (Polich).The TRSI-ARC research program will employ molecular, cellular, neuropharmacological and clinical research methods on Experimental animal subjects and human subjects. The overall hypothesis of the TSRI-ARC is that the function of specific neurotransmitter synapses in select parts of the reward and stress systems that are compromised by chronic ethanol administration account for the development of vulnerability to alcoholism in genetically prone individuals. Three major subthemes have emerged from our present research: 1) the neuropharrnacological mechanisms of vulnerability to dependence by identifying how specific brain reward and stress circuits change during the development of alcohol dependence, 2) the neuropharmacological changes that persist during protracted abstinence eventually leading to relapse to heavy drinking and 3) the neuropharmacological changes in reward and stress mechanisms that are responsible for the individual differences associated with a risk for development of dependence. Progress during the previous funding period has led to a focus on understanding dependence-induced neuroadaptive mechanisms involving corticotropin-releasing factor and neuropeptide Y systems and modulatory systems such as neuroactive steroids and endocannabinoids. Residual allostatic changes in the brain reward and stress neurocircuitry that persist following acute abstinence are envisioned as a crucial part of the basis for inheritable susceptibility to human alcoholism. The TSRI-ARC also supports the Center at Large which includes: 14 NIAAA, R01's, 1 NIAAA R23, 2 NIAAA K awards, 1 NIAAA training grant, and 2 NIAAA consortium core components. Training and information dissemination to the San Diego community will be effected by the training opportunities of the Center including an NIAAA training grant and the Education Component.